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Microbes & Immunity iPSC-derived NK cell immunotherapy

is highly expressed in multiple types of tumors and plays actually helps NK cells to detach from the dying target cells
a stimulatory role in the proliferation of cancer cells. and prepare them to kill the next target cells. Whether
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Through the overexpression of the CXCR4 receptor, it is this non-cleavable CD16 will have a better tumor-killing
possible to significantly facilitate CAR-NK cells targeting effect in the real world compared to the cleavable CD16
EGFRvIII, enabling them to migrate to CXCL12-secreting remains to be investigated further.
glioblastomas. The effectiveness of this approach has been IL-15 is an important cytokine for maintaining NK
validated through in vivo xenograft experiments with cell homeostasis and function, increasing the number
solid tumors. Intravenously administration of CXCR4 of CD56 bright NK cells and enhancing the cytotoxicity of
expressing CAR-modified NK cells further improves CD56 NK cells. 143,144 It is also an important target of
dim
survival of tumor-bearing animals compared to NK cells NK cell-centered cancer immunotherapy. However, the
only expressing EGFRvIII-specific CAR. To strengthen IL-15 is a short-lived, low-activity cytokine under normal
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the argument for the enhanced anti-tumor effects achieved physiological conditions. Previous studies have shown
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through ectopic expression of chemokine receptors, that the IL-15/IL-15R complex can release the function
acquiring more in vivo data and reinforcing the existing of NK cells from TGF-β inhibition. Activation of the
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preclinical evidence is essential. IL-15 signaling pathway in iPSC-derived NK cells can
4.4. Other methods utilizing iPSCs to enhance anti- be achieved through the fusion expression of IL-15Rα
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tumor functions of NK cell with IL-15, mimicking transpresentation. Although
NK cells overexpressing IL-15 are freed from autocrine
CD16 (FcγRIIIA) is uniformly expressed in peripheral cytokine dependence, their true tumor-killing ability to
CD56 NK cells and plays a crucial role in ADCC. resist immune suppression in solid tumors remains to be
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When cells are labeled with antibodies, NK cell cytotoxicity further investigated. The combination of IL-15, IL-18, and
is triggered through the Fc segment of the antibody, IL-12 has been used to stimulate NK cells, enhance NK cell
representing a notable example of adaptive immunity proliferation and activation, and produce IFN-γ, as well
augmenting innate immunity. In pre-clinical in vivo as to enhance the anti-tumor properties of NK cells. 143,148
experiments, the combination of anti-GD2 antibodies with CIS protein (cytokine-inducible SH2-containing protein),
NK cells has shown promising therapeutic efficacy. In a encoded by the CISH gene, can negatively regulate IL-15
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clinical trial targeting neuroblastoma, the use of anti-GD2 signaling in NK cells, and its deletion can improve the
monoclonal antibodies in conjunction with haploidentical metabolic activity of iPSC-derived NK cells. However,
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NK cells exhibited anti-cancer activity, particularly at recent studies have revealed that IL-15 may also contribute
higher doses. Given the unique properties of CD16, it has to the downregulation of certain chemokines, thereby
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risen as a key target for genetic engineering in the iPSC- influencing NK cell migration and function. CX3CR1
derived NK cell development. 137,138 Although CD16 can is present in nearly all CD16 CD56 bright NK cells and is
+
mediate ADCC, it is not a high-affinity Fc receptor. CD64 crucial for NK cell adhesion, chemotaxis, degranulation,
(FcγRI), on the other hand, has a higher affinity for IgG, and tumor cell killing. Both the surface expression and
but it is not expressed on NK cells. Studies have combined mRNA level of CX3CR1 are reduced in the presence of
CD64 and CD16 to create a new recombinant receptor. IL-15. 150,151 In proliferating NK cells activated by IL-15,
This receptor consists of a high-affinity antibody binding CX3CR1 expression is very low and may not function
to the extracellular region of human CD64, whereas the properly as a chemokine receptor. The reason for this is
transmembrane and intracellular regions of human CD16A not clear but it could be to protect normal endothelial
mediate NK cell signaling. After being equipped with cells from NK cell attack. Moreover, the enhancement
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CD64/16A, NK cells demonstrated significantly enhanced of NK cell migration and cytotoxic functions through
abilities in mediating ADCC, increased production of IFN- short-term hypoxia in conjunction with IL-15 suggests a
γ, and improved killing of target cells. CD16, however, is potential synergy that could be leveraged to augment anti-
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vulnerable to cleavage by metalloproteinases. This cleavage tumor responses. This insight underscores the necessity
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results in a somewhat reduced but still retained sensitivity for a more advanced approach to utilizing IL-15 within
of NK cells to other activating receptors. For instance, iPSC-derived NK cell therapies. Such strategies may need
metalloproteinase ADAM17, also known as TNF-α to carefully consider the intricate dynamics between
converting enzyme (131), can cause the loss of CD16 when IL-15, NK cell biology, and the tumor microenvironment
overexpressed on NK cells (132). To mitigate the issue of to optimize the therapeutic potential of NK cells
CD16 cleavage, a non-cleavable version of human CD16 against cancer. Methods for augmenting the anti-tumor
(hnCD16) was engineered. However, it is important capabilities of NK cells through genetic modification are
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to note that CD16, by mediating the break after ADCC, summarized in Figure 2.

Volume 2 Issue 1 (2025) 35 doi: 10.36922/mi.5653